Worldwide, patients with spinal muscular atrophy (SMA) may experience metabolic disorders affecting nucleotide metabolism, lipid, carbohydrate, amino acid, vitamin and cofactor regulation. Although the metabolic homeostasis status of this population requires further investigation, N-acetylneuraminic acid may be a potential treatment to counteract these effects in SMA. These findings are based on a case-control study recently published in the Italian Journal of Pediatrics.1
SMA has previously been associated with multiple metabolic and nutritional issues | Image credit: alionaprof -stock.adobe.com
Metabolic and nutritional issues have been previously documented to be outcomes observed in SMA patients, with metabolic abnormalities related to lipids, glucose, and individual vitamin levels cited as more common.2 The current study further explored these effects in a cohort of 15 SMA patients from December 2021 to September 2022, and compared them to a control group of 14.1 To identify metabolites in both groups, 2-mL samples of cerebrospinal fluid (CSF) were taken, and the researchers performed untargeted metabolomics. Patients with a history of treatment with nusinersen (Springraza), risdiplam (Evrisdi), or onasemnogene abeparvovec (Zolgensma) were excluded. After the initial samples were collected, measures such as partial least squares discriminant analysis (PLS-DA), principal component analysis (PCA), and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied in multivariate analyses.
In this cohort of SMA patients, 40% were female compared with 64% in the control group, and the mean age was 2.3 and 1.8 years, respectively. There was one patient with type 1 SMA, nine with type 2, and five with type 3. Furthermore, all patients in the SMA group had a spinal motor neuron (SMN) 1 exon 7 homozygous deletion, with five patients showing two SMN2 copies, eight patients showing three copies, and two patients showing four copies.
Multivariate analysis of metabolites “showed clear differences between all SMA patients and normal controls in both positive and negative ionization modes. These results indicate a significant alteration of the metabolic profile in CSF of SMA patients,” the authors wrote. Significant metabolite changes between groups were observed for 118 metabolites. The most significant differences were observed for N-acetylneuraminic acid (P = .0000549), 2,3-dihydroxyindole (P = .000181), lumichrome (P = .000079), arachidic acid (P = .0000065), and 10-hydroxydecanoic acid (P = .000144).
There were 11 different metabolites related to amino acid metabolism. SMA patients had lower concentrations of gamma-glutamylcysteine (P = .0000549), 2,3-dihydroxyindole (P = .000181), 4-hydroxycinnamoylagmatine (P = .000766), and phenylpyruvic acid (P = .00126). Conversely, concentrations of methylmalonic acid (P = .00173), urocanic acid (P = .00000374), 1-pyrroline-2-carboxylic acid (P = .000545), D-glutamine (P = .00281), guanidoacetic acid (P = .000721), fructose 1,6-bisphosphate (P = .00461), and quinic acid (P = .00211) were significantly higher in the SMA group.
Furthermore, in their analysis of the functional pathways of the differentially abundant metabolites, the authors reported that 35 of 118 have a role in amino acid metabolism, 21 in lipid metabolism, 11 in carbohydrate metabolism, 9 in vitamin and cofactor metabolism, and 7 in nucleotide metabolism.
“Dysregulation of amino acid, lipid, carbohydrate, cofactor, vitamin and nucleotide metabolism indicates a global breakdown in metabolic homeostasis in SMA patients, particularly in amino acid and lipid metabolism,” the authors conclude, adding that “N-acetylneuraminic acid may be a potential therapeutic agent for improving function in SMA patients.”
References
1. Zhuang W, Wang M, Lu M, et al. Dysregulation of cerebrospinal fluid metabolic profile in patients with spinal muscular atrophy: a case-control study. Ital J Pediatr. 2024;50(1):154. doi:10.1186/s13052-024-01726-6
2. Rosenberg J. SMA related with metabolic, nutritional issues. AJMC®. January 24, 2021. Accessed September 7, 2024. https://www.ajmc.com/view/sma-related-with-metabolic-nutritional-issues
